Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000697684
Ethics application status
Approved
Date submitted
9/06/2023
Date registered
30/06/2023
Date last updated
27/09/2023
Date data sharing statement initially provided
30/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Nutritional repletion before bariatric surgery trial
Scientific title
What is the feasibility of a pragmatic pilot randomised controlled trial to compare an intensive preoperative repletion schedule to standard care for private bariatric-metabolic surgery candidates in Australia?
Secondary ID [1] 309612 0
None
Universal Trial Number (UTN)
U1111-1292-4766
Trial acronym
NURTURE Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obesity 329932 0
Micronutrient deficiency 329933 0
Bariatric-metabolic surgery 330390 0
Condition category
Condition code
Surgery 326838 326838 0 0
Other surgery
Diet and Nutrition 326839 326839 0 0
Obesity

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
An intensive preoperative schedule to treat micronutrient deficiencies: patients with low vitamin D level will be referred to a medical practitioner with a recommended treatment of one intramuscular injection of 600,000 IU vitamin D3; patients with low folate level will be referred to a medical practitioner with a recommended treatment of one intramuscular injection of 15 mg folic acid; patients with low iron level (defined by ferritin and transferrin saturation index) will be referred to a medical practitioner with a recommended treatment of one intravenous infusion of 1 g iron; patients with either solely low thiamin level, solely low vitamin B12 level, or both will be referred to a medical practitioner with a recommended treatment of one intramuscular injection of B-Dose Forte containing 250 mg thiamin and 1 mg vitamin B12 (also containing B2 riboflavin sodium phosphate 5 mg, B3 nicotinamide 50 mg, B5 dexpanthenol 50 mg, B6 pyridoxine hydrochloride 100 mg); patients with solely low magnesium level will be referred to a medical practitioner with a recommended treatment of one intramuscular injection of 480 mg magnesium; patients with solely low zinc level will be referred to a medical practitioner with a recommended treatment of one intramuscular injection of 10.6 mg zinc; patients with low level of B vitamins plus magnesium and/or zinc, will be referred to a medical practitioner with a recommended treatment of one intramuscular injection or intravenous infusion of B Complex Forte with extra magnesium and/or zinc. Referrals for micronutrient infusions or injections will be made at least 14 days prior to sleeve gastrectomy. The referrals will request that in the event the medical practitioner agrees to the recommended infusions and/or injections and they are prescribed, that they are delivered by the medical practitioner (and/or their supervised nurse) 14 days prior to sleeve gastrectomy. Prescription of the recommended treatments by the medical practitioner will be monitored via medical notes and adherence to any prescribed treatments by the medical practitioner will be monitored by the medical notes or direct observation by the researcher.

Both the intervention and control arm will orally take one multivitamin and mineral supplement daily, and one calcium supplement daily for 14 days directly prior to sleeve gastrectomy. Multivitamin and mineral supplement contains: beta-carotene 2.3mg, retinol acetate 442.7 µg (vitamin A 375 µg RE), vitamin C 60 mg, cholecalciferol vitamin D3 500 IU, vitamin E 15 IU, thiamin nitrate 6 mg (thiamin 4.9 mg), riboflavin 5 mg, calcium pantothenate 5 mg (vitamin B5 4.6 mg), co-methylcobalamin vitamin B12 300 µg, vitamin B6 as pyridoxine hydrochloride 1.3 mg, calcium folate 347 µg (folic acid 250 µg), vitamin B3 25 mg, vitamin K1 70 µg, inositol 10 mg, iron (as ferrous fumarate) 12 mg, magnesium (as heavy magnesium oxide) 52.5 mg, iodine (as potassium iodide) 75 µg, copper (as cupric citrate hemipentahydrate) 374 µg, zinc (as zinc amino acid chelate) 7.5 mg, selenium (as selenomethionine) 15 µg, manganese (as manganese amino acid chelate) 1 mg, chromium (as chromium picolinate) 25 µg, total chromium 60 µg, choline bitrate 2.5 mg, molybdenum (as molybdenum trioxide) 37.5 µg, biotin 150 µg); Calcium supplement contains: calcium 500 mg, and vitamin D 12.5 µg (equivalent to 500 IU). Adherence to these oral supplements will be measured via interview and tablet/capsule counting at the end of the intervention period. The multivitamin and mineral supplement and calcium supplement is prescribed for 14 days directly prior to sleeve gastrectomy.

Medical, diet, and lifestyle conditions recommended as part of usual care will be monitored via medical records and brief participant surveys.
Intervention code [1] 326035 0
Treatment: Other
Comparator / control treatment
A usual care preoperative schedule to treat micronutrient deficiencies: patients with low vitamin D level will receive daily oral supplement of 6,000 IU vitamin D3 ; patients with low thiamin level will receive oral supplement in 250 mg thiamin nitrate tablets, once daily (equalling to 200 mg thiamin daily); patients with low folate level will receive oral supplement of 500 µg folic acid twice daily (equalling to 1,000 µg daily); patients with low vitamin B12 level will receive oral supplement vitamin B12 daily, 1 tablet of 1,000 µg daily; patient with low iron level (defined by ferritin and transferrin saturation index) will receive oral supplement of 100 mg elemental iron 2-3 times daily (being suggested to take separately from calcium and proton pump inhibitors); patients with low magnesium level will receive oral supplement of magnesium amino acid 500 mg twice daily (equalling to 220 mg elemental magnesium daily); patients with low zinc level will receive oral supplement of 30 mg elemental zinc daily. The treatments in the control arm will be delivered by researchers and given to patients 14 days directly prior to sleeve gastrectomy. Adherence to these oral supplements will be measured via interview and tablet/capsule counting at the end of the intervention period.

Both the intervention and control arm will orally take one multivitamin and mineral supplement daily, and one calcium supplement daily for 14 days directly prior to sleeve gastrectomy. Multivitamin and mineral supplement contains: beta-carotene 2.3mg, retinol acetate 442.7 µg (vitamin A 375 µg RE), vitamin C 60 mg, cholecalciferol vitamin D3 500 IU, vitamin E 15 IU, thiamin nitrate 6 mg (thiamin 4.9 mg), riboflavin 5 mg, calcium pantothenate 5 mg (vitamin B5 4.6 mg), co-methylcobalamin vitamin B12 300 µg, vitamin B6 as pyridoxine hydrochloride 1.3 mg, calcium folate 347 µg (folic acid 250 µg), vitamin B3 25 mg, vitamin K1 70 µg, inositol 10 mg, iron (as ferrous fumarate) 12 mg, magnesium (as heavy magnesium oxide) 52.5 mg, iodine (as potassium iodide) 75 µg, copper (as cupric citrate hemipentahydrate) 374 µg, zinc (as zinc amino acid chelate) 7.5 mg, selenium (as selenomethionine) 15 µg, manganese (as manganese amino acid chelate) 1 mg, chromium (as chromium picolinate) 25 µg, total chromium 60 µg, choline bitrate 2.5 mg, molybdenum (as molybdenum trioxide) 37.5 µg, biotin 150 µg); Calcium supplement contains: calcium 500 mg, and vitamin D 12.5 µg (equivalent to 500 IU). Adherence to these oral supplements will be measured via interview and tablet/capsule counting at the end of the intervention period. The multivitamin and mineral supplement and calcium supplement is prescribed for 14 days directly prior to sleeve gastrectomy.

Medical, diet, and lifestyle conditions recommended as part of usual care will be monitored via medical records and brief participant surveys.
Control group
Active

Outcomes
Primary outcome [1] 334720 0
The primary objective of this study is to test the feasibility of the methods. Data collection fidelity of study visits attendance will be assessed as part of study feasibility:
• Number of study visits attended / number required * 100.
Number of study visits attended will be assessed by an audit of the study visit schedule spreadsheet,
Timepoint [1] 334720 0
Primary outcome will be assessed at the following data collection timepoints:
T0: Baseline.
T1: Research treatment phase commences, 2+ weeks prior to the surgery. (Primary timepoint)
T2: Day of surgery.
T3: 4-14 days post-surgery.
Primary outcome [2] 335161 0
Retention rate will be assessed as part of study feasibility by an audit of the study recruitment spreadsheet:
Retention rate, expressed as a percentage, will be calculated as: Total number of participants – number of lost participants (withdrawn, removed, lost-to-follow-up) / total number of participants * 100.

In addition, the following information will be collected to help describe retention rate, by the audit of the study recruitment spreadsheet and a questionnaire containing one question asking the withdrawal reason.
• Timing, reason, and number of participants who withdraw from the study by T3;
• timing, reason and number of participants who are removed by the investigators by T2;
• timing, reasons if possible, and number lost to follow up (not attending study visits or data collection) by T3.
Timepoint [2] 335161 0
T1: Research treatment phase commences, 2+ weeks prior to the surgery. (Primary timepoint)
T2: Day of surgery.
T3: 4-14 days post-surgery.
Primary outcome [3] 335162 0
Participant adherence will be assessed as part of study feasibility: Investigator observation of intervention delivery (infusions and injections), participant self-report (oral supplements), and pill counting (supplements). Participants will be considered adherent if they accept the infusion or injection if prescribed by the GP and/or if they consume > or = 80% of the recommended oral supplements.
Timepoint [3] 335162 0
T1: Research treatment phase commences, 2+ weeks prior to the surgery. (Primary timepoint)
T3: 4-14 days post-surgery.
Secondary outcome [1] 422680 0
Safety will be measured by adverse events expressed by rate, type, and severity. Events will be measured by medical record monitoring and self-reported safety questionnaire; then categorised by investigators. Examples of adverse events include nausea (type: gastrointestinal, severity: mild), allergic reaction - rash (type: medical, severity: moderate).
Timepoint [1] 422680 0
Assessed from 14 days prior to the surgery (T1), the day of surgery (T2) and at T3: 4-14 days post-surgery.
Secondary outcome [2] 422681 0
Due to the nature of the study (i.e., a pilot), this outcome will be reported as a composite secondary outcome. The preliminary efficacy will be measured by the change in total number of deficiencies of multiple micronutrients (25OHD, thiamin, folate, vitamin B12, ferritin, iron, total iron binding capacity, magnesium, and zinc) between baseline and follow-ups (at day of surgery, 6-month post-surgery, and 12-month post-surgery). Blood samples of participants will be collected and analysed by a third-party accredited laboratory.
Timepoint [2] 422681 0
T0: baseline, T2: day of surgery, 6-month post-surgery, and 12-month post-surgery.
Secondary outcome [3] 422682 0
Quality of life will be measured by the valid and reliable EQ-5D-5L.
Timepoint [3] 422682 0
T0: baseline and T3: 4-14 days post-surgery.
Secondary outcome [4] 422683 0
Fatigue levels will be assessed via the valid PROMIS Item Bank v1.0 – Fatigue – Short Form 7a tool.
Timepoint [4] 422683 0
T0: baseline and T3: 4-14 days post-surgery.
Secondary outcome [5] 422684 0
Sleep quality will be assessed via the valid PROMIS Item Bank v1.0 – Sleep Disturbance – Short Form 8b tool.
Timepoint [5] 422684 0
T0: baseline and T3: 4-14 days post-surgery.
Secondary outcome [6] 423321 0
This is a primary outcome. Recruitment rate will be assessed as part of study feasibility:
• Total number of participants randomised / the number of months of recruitment time.
• Participants consented at phase I recruitment / Total number of eligible participants at phase I recruitment * 100.
• Participants eligible at phase II recruitment / Total number of consented participants at phase I recruitment * 100.
Timepoint [6] 423321 0
T0: Baseline.
T1: Research treatment phase commences, 2+ weeks prior to the surgery. (Primary timepoint)
Secondary outcome [7] 423322 0
This is a primary outcome. Randomisation success will be assessed as part of study feasibility: No statistically significant difference between groups in terms of age, sex, and body mass index (BMI).
Timepoint [7] 423322 0
T0: Baseline.
Secondary outcome [8] 423323 0
This is a primary outcome. Intervention fidelity will be assessed as part of study feasibility: The fidelity to the repletion schedule will be measured by comparing actual repletion received against the repletion recommended in the relevant schedule, according to group allocation. Deviated steps will be recorded by investigators in a deviation record (Microsoft Excel spreadsheet).
• Number of deviations from standard operating procedure (SOP) / total number of steps in SOP * 100 (calculated per participant; measures of central tendency and variation reported).
Timepoint [8] 423323 0
T0: Baseline.
T1: Research treatment phase commences, 2+ weeks prior to the surgery. (Primary timepoint)
T2: Day of surgery.
T3: 4-14 days post-surgery.
Secondary outcome [9] 423503 0
This is a primary outcome. Data collection fidelity of outcome assessment will be assessed as part of study feasibility:
• Number of missing outcome measures / number required * 100.
Number of missing outcome measures will be assessed by an audit of data collection tools and the study recruitment spreadsheet.
Timepoint [9] 423503 0
Primary outcome will be assessed at the following data collection timepoints:
T0: Baseline.
T1: Research treatment phase commences, 2+ weeks prior to the surgery. (Primary timepoint)
T2: Day of surgery.
T3: 4-14 days post-surgery.

Eligibility
Key inclusion criteria
1. Human adults aged 18-65 years.
2. Have elected sleeve gastrectomy as their primary surgery at the recruitment site (a private clinic).
3. Based on a preoperative blood test, has been identified as having at least one of the following micronutrient deficiencies: thiamin, folate, vitamin B12, vitamin D, iron, magnesium, or zinc.
4. BMI 30.0-50.0 kg/m2 2+ weeks prior to surgery.
5. Be willing to accept injection, infusion, and/or oral supplementation as micronutrient repletion strategies.
6. Be willing to stop all non-study related nutritional supplements, herbal preparations, and probiotics from the date of recruitment until Day 1 post-surgery.
7. Be willing to attend three appointments in person at the private clinic: two preoperative and one postoperative appointment. I.e., only local and available participants eligible.
8. 2-week intervention phase is feasible based on eligibility confirmation and surgery date.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Medical history of gastrointestinal conditions associated with malabsorption, e.g., coeliac disease, inflammatory bowel disease.
2. Cannot speak, read, or write English.
3. Psychiatric disorder associated with decreased ability to adhere to or tolerate the study conditions, as indicated by the treating psychologist.
4. Patients with known allergy(ies) to vitamin and/or mineral supplementation.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
An investigator independent from the intervention will create a computer-generated number list and upload to REDCap. Allocations will be saved to a password protected Excel file accessible only to PI Reidlinger and PI Marshall and will be made available to the study team at study conclusion.

Once eligibility has been confirmed, the participant will be allocated to intervention or control via REDCap. The investigator/s who are responsible for delivering repletion schedule will be concealed from allocation by disabling the rights to set-up and randomisation of the randomisation module in REDCap. The investigator/s will only be able to access the dashboard of the randomisation module when being notified the results of randomisation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation and group allocation will be conducted using REDCap electronic data capture tools hosted at Bond University. Participants will be randomly allocated to either the intervention arm or control arm in a 1:1 ratio via a simple randomisation strategy, stratifying for key demographic variables.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
SPSS will be used to statistically analyse data. Continuous variables will be presented as mean ± SD or medians (interquartile range), and categorical variables will be presented as proportions.

The primary outcome (repletion schedule feasibility) data, rates of micronutrient deficiency, and adverse event data will be presented as frequencies and percentages and compared between groups using chi-square for categorical outcomes and independent t-tests for parametric continuous data (or Mann-Whitney U test for non-parametric). Baseline, follow-up, and changes in quality of life, fatigue, and sleep quality scores will be descriptively reported and differences in score changes between intervention and control arm will be determined by independent-samples t-test (or non-parametric equivalent if required).
For biochemistry data, if assumptions of parametric tests are met, between-group differences at follow-ups will be determined by analysis of covariance (ANCOVA), after accounting for baseline micronutrient levels and within-group difference between baseline and follow-ups will be determined by one-way repeated measures analysis of variance (ANOVA). If only non-parametric tests are suitable to be applied, between-group differences will be determined by Kruskal-Wallis test and within-group differences will be determined by Friedman test.

Within-group changes from baseline in continuous outcome data will be tested by paired-samples t-test (or another non-parametric test if required) or McNemar’s test for categorical data.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
17/07/2023
Actual
7/08/2023
Date of last participant enrolment
Anticipated
31/12/2023
Actual
Date of last data collection
Anticipated
28/02/2026
Actual
Sample size
Target
40
Accrual to date
6
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment postcode(s) [1] 40516 0
4227 - Varsity Lakes

Funding & Sponsors
Funding source category [1] 313792 0
University
Name [1] 313792 0
Doctor of Philosophy (Faculty of Health Sciences and Medicine, Bond University)
Country [1] 313792 0
Australia
Primary sponsor type
University
Name
Bond University
Address
14 University Drive, Robina Queensland 4226
Country
Australia
Secondary sponsor category [1] 315911 0
None
Name [1] 315911 0
Address [1] 315911 0
Country [1] 315911 0
Other collaborator category [1] 282694 0
Commercial sector/Industry
Name [1] 282694 0
WeightLoss Solutions Australia
Address [1] 282694 0
Suite 3 Podium Level, Lakeside 1, Bermuda Point, 1 Lake Orr Drive, Varsity Lakes Queensland 4227
Country [1] 282694 0
Australia
Other collaborator category [2] 282695 0
Commercial sector/Industry
Name [2] 282695 0
Research Institute for Future Health
Address [2] 282695 0
1 Lake Orr Dr Suite 3, Podium Level Lakeside 1 Varsity Lakes, Queensland 4227
Country [2] 282695 0
Australia
Other collaborator category [3] 282696 0
Commercial sector/Industry
Name [3] 282696 0
Nutrition Research Australia
Address [3] 282696 0
20 Martin Pl, Sydney, New South Wales, 2000
Country [3] 282696 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312959 0
Bond University Human Research Ethics Committee
Ethics committee address [1] 312959 0
14 University Drive, Robina Queensland 4226
Ethics committee country [1] 312959 0
Australia
Date submitted for ethics approval [1] 312959 0
10/02/2023
Approval date [1] 312959 0
25/05/2023
Ethics approval number [1] 312959 0
XT00002

Summary
Brief summary
Many patients who have bariatric surgery already have micronutrient (vitamin and mineral) deficiencies before their surgery. However, there is no standard approach to how deficiencies are corrected. This pilot study is conducted to test the feasibility of our methods before conducting a larger study. Participants will be randomised (will not be given a choice) to one of two groups. The intervention group will be referred to a medical practitioner to have their deficiencies treated via infusions and/or injections, alongside multivitamin and calcium tablets for two weeks. The comparator group will receive relevant vitamin and mineral tablets to correct their deficiencies. They will take these tablets, as well as multivitamin and calcium tablets for two weeks. We hypothesise in this pilot study, that a larger study will be feasible to be conducted in a private clinic setting.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126486 0
A/Prof Dianne P Reidlinger
Address 126486 0
Bond University, Faculty of Health Sciences and Medicine.

14 University Drive, Robina Queensland 4226
Country 126486 0
Australia
Phone 126486 0
+61 0755955530
Fax 126486 0
Email 126486 0
dreidlin@bond.edu.au
Contact person for public queries
Name 126487 0
A/Prof Dianne P Reidlinger
Address 126487 0
Bond University, Faculty of Health Sciences and Medicine.

14 University Drive, Robina Queensland 4226
Country 126487 0
Australia
Phone 126487 0
+61 0755955530
Fax 126487 0
Email 126487 0
dreidlin@bond.edu.au
Contact person for scientific queries
Name 126488 0
A/Prof Dianne P Reidlinger
Address 126488 0
Bond University, Faculty of Health Sciences and Medicine.

14 University Drive, Robina Queensland 4226
Country 126488 0
Australia
Phone 126488 0
+61 0755955530
Fax 126488 0
Email 126488 0
dreidlin@bond.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
We plan to make the data available, in deidentified format, for other researchers to use the data
in future research in this under-researched area. This will include de-identified individual participant data of primary outcomes and secondary outcomes.
When will data be available (start and end dates)?
The data will be available after the results of the study have been published, and until 5 years after publication.
Available to whom?
Any interested parties.
Available for what types of analyses?
Any purpose.
How or where can data be obtained?
To access the data, interested parties should make a written request to the Chief Investigator, Dr Dianne Reidlinger (email: dreidlin@bond.edu.au). Decisions to share the data will be made by the Chief Investigator in conjunction with the Chair, Bond University Human Research Ethics Committee.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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